The proposed project will attempt to gain insight into parasite activated oxygen defenses as well as uncover new leads for the development of antiparasitic drugs through a study of the superoxide dismutases (SOD's) of leishmania and trypanosomes. We have found that leishmania and trypanosomes have iron-containing SOD's in contrast to their mammalian hosts which have copper, zinc-containing and manganese-containing SOD's (37,53). We have purified an Fe-SOD from the related trypanosomatid, Crithidia fasciculata (57) and have found several chelators and oxidizing agents which inhibit it without affecting host Cu,Zn-SOD. We will now search for better and more selective leishmanial and trypanosomal SOD inhibitors which may have chemotherapeutic potential. In order to accomplish this we will: 1) undertake biochemical studies of the enzyme to identify vulnerable functional groups, 2) study the mechanisms by which chelators and oxidizing agents inhibit crithidial SOD, 3) analyze structure-activity relationships among SOD inhibitors, 4) evaluate the importance of SOD in trypanosomes and leishmania, and 5) measure SOD turnover in whole organisms in the presence and absence of oxidative stress.